The present invention relates generally to the treatment of patients. More specifically, the present invention relates to reducing or preventing bone marrow hypoplasia.
Presently, 3'-Azidothymidine (AZT) is the primary therapy for the treatment of AIDS. AZT is an antiretroviral drug that is active against human immunodeficiency virus (HIV). In this regard, AZT is an inhibitor of the in vitro replication of some retroviruses, including HIV. AZT is marketed by the Burroughs Wellcome Company under the name Retrovir. Retrovir is the brand name for Zidovudine (formerly called azidothymidine (AZT)). See Physician Desk Reference, 44th Edition, 1990, pg. 799.
Recently, attention has been focussed on another potential treatment for AIDS using DDI. DDI is also an antiretroviral drug.
Unfortunately, AZT has a significant dose dependent toxicity. In fact, the 1990 PDR bears the following statement:
Warning Therapy with Retrovoir (Zidovudine) is often associated with hematologic toxicity including granulocytopenia and severe anemia requiring transfusions (see warnings).
AZT related bone marrow toxicity limits the utility of the drug. See, Thompson et al, "Hematologic Toxicity of AZT and ddC Administered as Single Agent and in Combination to Rats and Mice", Fundamental and Applied Toxicity, 17,159-176 (1991). Although the basis of the toxicity is not completely understood, some evidence suggests a metabolite of AZT, 3'-amino-3'-deoxythymidine (AMT), may be at least partially responsible. See, Cretton, "Catabolism of 3'-Azido-3'-deoxythymidine in Hepatocytes in Liver Microsomes, with Evidence of Formation of 3'-Amino-3'-deoxythymidine, a Highly Toxic Catabolite for Human Bone Marrow Cells", Molecular Pharmacology, 39:258-266. It has been reported that some thiols, including reduced glutathione, can reduce AZT to AMT in vivo. See, Handlon et al, "Thiol Reduction of 3'-Azidothymidine to 3'-Aminothymidine: Kinetics and Biomedical Implications", Pharmaceutical Research, Vol. 5, No. 5, 1988.
Additionally, long term administration of AZT can cause mitochondrial mycotoxicity. See, Lamperth et al, "Abnormal Skeletal and Cardiac Muscle Mitochondria Induced by Zidovudine (AZT) in Human Muscles In Vitro and in Animal Model" Laboratory Investigation, 1991, 65:742 This results in a myopathy that develops after a mean period of 12 months of therapy. Id.
Further adverse reactions have been reported with AZT. Additionally, DDI has been reported to also cause a variety of severe adverse reactions.
Due to the dose dependent toxicity of AZT and DDI the effectiveness of these drugs as therapies in treating AIDS has been limited.
Bone marrow hypoplasia can occur due to a number of reasons in addition to antiretroviral therapy. Although rare, aplastic or hypoplastic anemia is characterized by anemia with decrease of marrow mass. See, Merck Manual, page 1153.
Additionally, many insults or treatments can result in bone marrow hypoplasia. Chemotherapy, as well as radiation therapy, can cause bone marrow hypoplasia. Even non-chemotherapy and non-antiretroviral therapies have been implicated in individual cases of bone marrow hypoplasia (for example: antibiotics; anti-inflammatory drugs; and anti-convulsants). See, Merck Manual, page 1153.
Likewise, a number of chemical entities (e.g., benzene and inorganic arsenic) have been linked to bone marrow hypoplasia. Id. Still further, bone marrow hypoplasia may be found in the elderly. Id.